Dataset Information

Long-term risk associated with clonal hematopoiesis in patients with severe aortic valve stenosis undergoing TAVR.

ABSTRACT:

Background

Mutations in the clonal hematopoiesis of indeterminate potential (CHIP)-driver genes DNMT3A and TET2 have been previously shown to be associated with short-term prognosis in patients undergoing TAVR for aortic valve stenosis. We aimed to extend and characterize these findings on long-term outcome in a large cohort.

Methods

A total of 453 consecutive patients undergoing TAVR were included in an up to 4-year follow-up study. Next-generation sequencing was used to identify DNMT3A- and/or TET2-CHIP-driver mutations. Primary endpoint was all-cause mortality. Since CHIP-driver mutations appear to be closely related to DNA methylation, results were also assessed in patients who never smoked, a factor known to interfere with DNA methylation.

Results

DNMT3A-/TET2-CHIP-driver mutations were present in 32.4% of patients (DNMT3A n = 92, TET2 n = 71), and were more frequent in women (52.4% vs. 38.9%, p = 0.007) and older participants (83.3 vs. 82.2 years, p = 0.011), while clinical characteristics or blood-derived parameters did not differ. CHIP-driver mutations were associated with a significantly higher mortality up to 4 years after TAVR in both univariate (p = 0.031) and multivariate analyses (HR 1.429, 95%CI 1.014-2.013, p = 0.041). The difference was even more pronounced (p = 0.011) in never smokers. Compared to TET2 mutation carriers, patients with DNMT3A mutations had significantly less frequently concomitant coronary and peripheral artery disease.

Conclusion

DNMT3A- and TET2-CHIP-driver mutations are associated with long-term mortality in patients with aortic valve stenosis even after a successful TAVR. The association is also present in never smokers, in whom no biasing effect from smoking on DNA methylation is to be expected.

SUBMITTER: Mas-Peiro S

PROVIDER: S-EPMC10160205 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Publications

Long-term risk associated with clonal hematopoiesis in patients with severe aortic valve stenosis undergoing TAVR.

Mas-Peiro Silvia S Pergola Graziella G Berkowitsch Alexander A Meggendorfer Manja M Rieger Michael A MA Vasa-Nicotera Mariuca M Dimmeler Stefanie S Zeiher Andreas M AM

Clinical research in cardiology : official journal of the German Cardiac Society 20230121 5

<h4>Background</h4>Mutations in the clonal hematopoiesis of indeterminate potential (CHIP)-driver genes DNMT3A and TET2 have been previously shown to be associated with short-term prognosis in patients undergoing TAVR for aortic valve stenosis. We aimed to extend and characterize these findings on long-term outcome in a large cohort.<h4>Methods</h4>A total of 453 consecutive patients undergoing TAVR were included in an up to 4-year follow-up study. Next-generation sequencing was used to identify ...[more]

PMID: 36680616

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Project description:ImportanceCytokine release syndrome is a complication of coronavirus disease 2019. Clinically, advanced age and cardiovascular comorbidities are the most important risk factors.ObjectiveTo determine whether clonal hematopoiesis of indeterminate potential (CHIP), an age-associated condition with excess cardiovascular risk defined as the presence of an expanded, mutated somatic blood cell clone in persons without other hematological abnormalities, may be associated with an inflammatory gene expression sensitizing monocytes to aggravated immune responses.Design, setting, and participantsThis hypothesis-generating diagnostic study examined a cohort of patients with severe degenerative aortic valve stenosis or chronic postinfarction heart failure, as well as age-matched healthy control participants. Single-cell RNA sequencing and analyses of circulating peripheral monocytes was done between 2017 and 2019 to assess the transcriptome of circulating monocytes.ExposuresSevere degenerative aortic valve stenosis or chronic postinfarction heart failure.Main outcomes and measuresCHIP-driver sequence variations in monocytes with a proinflammatory signature of genes involved in cytokine release syndrome.ResultsThe study included 8 patients with severe degenerative aortic valve stenosis, 6 with chronic postinfarction heart failure, and 3 healthy control participants. Their mean age was 75.7 (range, 54-89) years, and 6 were women. Mean CHIP-driver gene variant allele frequency was 4.2% (range, 2.5%-6.9%) for DNMT3A and 14.3% (range, 2.6%-37.4%) for TET2. Participants with DNMT3A or TET2 CHIP-driver sequence variations displayed increased expression of interleukin 1β (no CHIP-driver sequence variations, 1.6217 normalized Unique Molecular Identifiers [nUMI]; DNMT3A, 5.3956 nUMI; P < .001; TET2, 10.8216 nUMI; P < .001), the interleukin 6 receptor (no CHIP-driver sequence variations, 0.5386 nUMI; DNMT3A, 0.9162 nUMI; P < .001;TET2, 0.5738 nUMI; P < .001), as well as the NLRP3 inflammasome complex (no CHIP-driver sequence variations, 0.4797 nUMI; DNMT3A, 0.9961 nUMI; P < .001; TET2, 1.2189 nUMI; P < .001), plus upregulation of CD163 (no CHIP-driver sequence variations, 0.5239 nUMI; DNMT3A, 1.4722 nUMI; P < .001; TET2, 1.0684 nUMI; P < .001), a cellular receptor capable of mediating infection, macrophage activation syndrome, and other genes involved in cytokine response syndrome. Gene ontology term analyses of regulated genes revealed that the most significantly upregulated genes encode for leukocyte-activation and interleukin-signaling pathways in monocytes of individuals with DNMT3A (myeloid leukocyte activation: log[Q value], -50.1986; log P value, -54.5177; regulation of cytokine production: log[Q value], -21.0264; log P value, -24.1993; signaling by interleukins: log[Q value], -18.0710: log P value, -21.1597) or TET2 CHIP-driver sequence variations (immune response: log[Q value], -36.3673; log P value, -40.6864; regulation of cytokine production: log[Q value], -13.1733; log P value, -16.3463; signaling by interleukins: log[Q value], -12.6547: log P value, -15.7977).Conclusions and relevanceMonocytes of individuals who carry CHIP-driver sequence variations and have cardiovascular disease appear to be primed for excessive inflammatory responses. Further studies are warranted to address potential adverse outcomes of coronavirus disease 2019 in patients with CHIP-driver sequence variations.

Dataset Information

Long-term risk associated with clonal hematopoiesis in patients with severe aortic valve stenosis undergoing TAVR.

Background

Methods

Results

Conclusion

Publications

Long-term risk associated with clonal hematopoiesis in patients with severe aortic valve stenosis undergoing TAVR.

Similar Datasets

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